ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.142G>A (p.Glu48Lys) (rs199473048)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058423 SCV000089943 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000678959 SCV000805175 uncertain significance Brugada syndrome 1 2018-05-11 criteria provided, single submitter clinical testing
GeneDx RCV000183168 SCV000235584 uncertain significance not provided 2018-11-29 criteria provided, single submitter clinical testing The E48K variant has been reported previously in one individual who was referred for LQTS genetic testing, and was absent from more than 2,600 alleles from control individuals of various ethnic backgrounds (Kapplinger et al., 2009). The E48K variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, missense variants in nearby residues (R43Q, P52S, R53Q) have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), supporting the functional importance of this region of the protein. The E48K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species and Lysine is the wildtype amino acid at this position in at least one species. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000638715 SCV000760257 uncertain significance Brugada syndrome 2018-03-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 48 of the SCN5A protein (p.Glu48Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs199473048, ExAC 0.02%). This variant has been reported in an individual referred for testing for long QT syndrome (LQTS) (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67663). Experimental studies have shown that this missense change behaved as wild-type in electrophysiological studies (PMID: 25904541). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825449 SCV000966750 uncertain significance not specified 2018-06-04 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Glu48Lys vari ant in SCN5A has been reported in one individual with LQTS (Kapplinger 2009) and in 16/274964 of total chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs199473048). Computational prediction to ols and conservation analysis do not provide strong support for or against an im pact to the protein; however, gorillas carry a lysine (Lys) at this position, ra ising the possibility that this change may be tolerated. In addition, in vitro s tudies suggest that this variant does not impact Nav1.5 channel function; howeve r, these types of assays may not accurately represent biological function (Kappl inger 2015; Anderson 2017). In summary, while the clinical significance of the p.Glu48Lys variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP criteria applied: BS1_supporting.

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